Received: 25 October 2019 Revised: 7 May 2021 Accepted: 4 July 2021

DOI: 10.1111/eip.13202

REVIEW ARTICLE

Efficacy of long-acting injectable versus oral antipsychotic

drugs in early psychosis: A systematic review and
meta-analysis

Lulu Lian1 | David D. Kim1,2 | Ric M. Procyshyn2,3 | Diane H. Fredrikson3 |

Diana Cázares4 | William G. Honer2,3 | Alasdair M. Barr1,2

1
Department of Anesthesiology,
Pharmacology & Therapeutics, University of
British Columbia, Vancouver, British Columbia,
Canada
2 to oral antipsychotics (OAPs) in individuals with psychosis who demonstrate poor
British Columbia Mental Health & Substance
Use Services Research Institute, Vancouver,
British Columbia, Canada
3
Department of Psychiatry, University of
British Columbia, Vancouver, British Columbia,
Canada
4
Department of Chemical & Biological
Sciences, Universidad de las Americas Puebla,
Puebla, Mexico
Correspondence
Alasdair M. Barr, Department of
Anesthesiology, Pharmacology & Therapeutics,
University of British 14 Columbia, Vancouver,
BC, Canada.
Email: al.barr@ubc.ca
Abstract
Aim: Long-acting injectable antipsychotic drugs (LAIs) are often used as an alternative
medication adherence. Previous meta-analyses have found mixed results on the effi-
cacy of LAIs, compared to OAPs, in patients with psychotic disorders. The objective
of this meta-analysis was to compare the effectiveness of using LAIs versus OAPs in
the early stages of psychosis.
Methods: Major electronic databases were used to search for any studies examining
the comparative effectiveness (i.e., relapse, adherence, hospitalization, and all-cause
discontinuation) of any LAIs versus OAPs in early stages of psychosis. Studies publi-
shed up to 6 June, 2019 were included and no language restriction was applied.
Inclusion criteria were a diagnosis of schizophrenia or related disorder, where
patients were in their first episode or had a duration of illness ≤5 years. Data were
analysed using a random-effects model.
Results: Fifteen studies (n = 10 584) were included, of which were 7 RCTs, 7 obser-
vational studies, and 1 post-hoc analysis. We found that LAIs provided advantages
over OAPs in terms of relapse rates. No significant differences were found between
LAI and OAP groups in terms of all-cause discontinuation, hospitalization, and adher-
ence rates. However, considering only RCTs revealed advantages of LAIs over OAPs
in terms of hospitalization rates.
Conclusions: LAIs may provide benefits over OAPs with respect to reducing relapse
and hospitalization rates in early psychosis patients. There is a need for larger and
better-designed studies comparing OAPs and LAIs specifically in early psychosis
patients.

KEYWORDS
antipsychotic, long-acting injectable, meta-analysis, oral antipsychotic, psychosis,
schizophrenia

Early Intervention in Psychiatry. 2021;1–11. wileyonlinelibrary.com/journal/eip © 2021 John Wiley & Sons Australia, Ltd. 1
2 LIAN ET AL.
1 | I N T RO DU CT I O N
Psychosis is a psychiatric condition that reflects a loss of touch with
reality, and includes symptoms such as hallucinations, delusions, avo-
lition, and anhedonia (Hany et al., 2019). The first episode of psycho-
sis typically occurs between the late teenage years and early twenties,
and represents an intensely stressful period for individuals and their
families, often requiring specialized psychiatric care and support ser-
vices (Iyer et al., 2015; Nordentoft et al., 2014). It has been reported
that a longer duration of untreated psychosis is related to worse clini-
cal outcomes in patients with schizophrenia (Friis et al., 2016; Murru &
Carpiniello, 2018; Perkins et al., 2005). Thus, it is important for early
intervention to be prioritized, as it may lead to a greater medication
response, and increase the chances of reaching remission (Larsen
et al., 2000).
Antipsychotic medications are commonly used to treat psy-
chotic symptoms during early psychosis, and can help prevent future
psychotic episodes (Hui et al., 2018). Current guidelines for early
psychosis recommend using atypical antipsychotics such as risperi-
done, aripiprazole and quetiapine as a first-line therapy (Keating
et al., 2017; Remington et al., 2017). A majority of first-episode psy-
chosis (FEP) patients respond to treatment with antipsychotics;
however, nonadherence to antipsychotics is a major clinical issue,
and has been demonstrated to occur in a significant proportion of
FEP patients during their first year of treatment (Coldham
et al., 2002; Dufort & Zipursky, 2019; Hickling et al., 2018). This rep-
resents a major concern, as relapse is common in the first few years
following the first episode of psychosis, and nonadherence to medi-
cation may contribute to more frequent relapses (Hui et al., 2013;
Verdoux et al., 2000). Relapses are not only highly stressful events
for individuals with psychosis, but recent evidence also suggests
they may contribute to long-term treatment resistance (Takeuchi
et al., 2019).
Many factors are associated with nonadherence behaviour,
including medication formulation and dosage frequency, treatment
cost, denial/minimization of illness, illness duration and phase, and
adverse effects (Kane et al., 2013). Depot antipsychotic drugs, also
known as long-acting injectables (LAIs), are often used to address the
issue of medication nonadherence in psychiatric patients (Correll
et al., 2016; Pietrini et al., 2019; Procyshyn et al., 2010). Advantages
of LAI antipsychotics over oral formulations may include increased
compliance, fewer side-effects, more stable plasma drug concentra-
tions, and consistent contact with medical professionals
(Gerlach, 1994). However, in many countries, only a relatively small
proportion of psychiatrists prescribe LAI antipsychotics to FEP
patients (Jaeger & Rossler, 2010).
Recent meta-analyses have found mixed results on the clinical
advantages of LAIs over oral antipsychotics (OAPs) in patients with
long-term, adult schizophrenia (Kishimoto et al., 2013; Kishimoto
et al., 2014; Kishimoto et al., 2018; Leucht et al., 2011; Ostuzzi
et al., 2017; Park et al., 2018), although the effects in early psychosis
remain largely unexamined. Kishi and colleagues (2016) conducted a
meta-analysis of randomized controlled trials (RCTs) comparing the
efficacy of LAIs and OAPs in patients with recent-onset psychotic
disorders. Their meta-analysis showed that LAIs were not superior
to OAPs for relapse prevention, all-cause discontinuation rates,
adverse events, or positive and negative syndrome scale (PANSS)
scores. On the other hand, they found that LAIs provided advan-
tages over OAPs in terms of discontinuation due to inefficacy and
nonadherence. However, because (Kishi et al., 2016) only allowed
the inclusion of RCTs in their meta-analysis, the number of studies
included in their analysis was small. In order to allow the inclusion of
a larger number of studies, the present meta-analysis includes both
RCTs and observational studies. The goal of this meta-analysis is to
compare the efficacy of LAIs versus OAPs in terms of adherence,
relapse, rehospitalization, and discontinuation rates in early psychosis
patients.
2 | METHODS
2.1 | Search strategy and study selection
We conducted a search for studies evaluating the efficacy of LAIs ver-
sus OAPs in early psychosis patients. The systematic review and
meta-analysis were conducted according to the preferred reporting
items for systematic reviews and meta-analyses guidelines (PRISMA)
2009 (Moher et al., 2009) as per our group have done previously for
other antipsychotic reviews (Linton et al., 2013; Whitney et al., 2015).
Relevant studies published from database inception to 6 June, 2019
were identified using EMBASE (Ovid), MEDLINE (Ovid), PsycINFO
(EBSCOhost), and Web of Science Core. The following MeSH terms
or keywords were used in the search: (1) [‘neuroleptic agentMESH’ OR
‘antipsychotic*’ OR ‘anti-psychotic*’] AND (2) [‘depot’ OR ‘long-act-
ing’ OR ‘long acting’] AND (3) ‘[first-episode psychosis OR first epi-
sode psychosis OR early psychosis OR early psychotic OR first
psychotic episode OR recent-onset OR recent onset]. Additional stud-
ies were identified by searching the reference lists of relevant publica-
tions. No restrictions were placed on language, year, age, sex,
ethnicity, setting, or trial duration. Two authors (LL and DC) indepen-
dently screened the titles and abstracts of the studies and evaluated
the full texts of the remaining eligible studies. Disagreements were
discussed and resolved by agreement or discussion with another
reviewer (DDK).
We included all studies that compared the use of LAIs and OAPs
in first-episode, recent-onset or early psychosis patients. Definitions
of early, recent-onset, and first-episode psychosis were based on the
criteria outlined by the study authors. If there was no specific defini-
tion provided, we selected studies that included patients with a mean
duration of illness ≤5 years. Studies were excluded from the meta-
analysis if patients were receiving OAP and LAIs concomitantly. All
study designs were considered for inclusion in the meta-analysis due
to the limited number of studies available on the selected topic. In
cases where multiple publications provided data from the same study
or patient population, the newer and more extensive study was
included.
LIAN ET AL.
2.2 | Data extraction and outcome measures
Data were independently extracted by two authors (LL and DC). Infor-
mation extracted from the studies included author information, year
of publication, study design, trial duration, sample size, demographics
(mean age, sex, ethnicity, diagnoses, duration of illness, comorbidities),
antipsychotic used (including formulation), concomitant medications,
medication dosages, and the primary outcomes of interest. Our pri-
mary outcomes of interest included hospitalization, adherence, all-
cause discontinuation, and relapse rates. We used the criteria for
adherence and relapse as outlined by the study authors.
2.3 | Data synthesis and analysis
Data analysis was carried out using the Cochrane Review Manager
(RevMan version 5.3, Cochrane Collaboration, Oxford, UK). Outcomes
of interest were analysed as dichotomous measures. If necessary, con-
tinuous and dichotomous outcomes were combined using an inverse
variance method outlined in the Cochrane Handbook for Systematic
Reviews of Interventions (9.4.6) ( Higgins & Green, 2011). We used a
random effects model to compare LAIs with OAPs. Subgroup analyses
were also performed to compare studies that included first-generation
antipsychotics (FGAs) with those that included second-generation
FIGURE 1 PRISMA flow
diagram
3
antipsychotics (SGAs), as well as to compare RCTs versus
observational studies. Heterogeneity was evaluated using the Higgins
I2 statistic. Substantial heterogeneity amongst studies was indicated
in cases where the I2 value was greater than 50% (Higgins
et al., 2003). Two authors (LL and DDK) independently assessed risk
of bias in RCTs using the Cochrane Risk of Bias tool (Higgins &
Green, 2011) and in observational studies using the risk of bias in non-
randomized studies–of interventions (ROBINS-I) (Sterne et al., 2016).
The assessment was not feasible in one study that was a post-hoc
comparison of two separate studies (Emsley et al., 2008), where one
was an RCT without an LAI group and the other was an LAI study
without a comparison group.
3 | RE SU LT S
3.1 | Search results and study characteristics
The literature search yielded 319 publications, and four additional
publications were identified through searching the reference lists of
relevant articles (Figure 1). After excluding duplicates, 250 articles
remained. A total of 15 studies (Abdel-Baki et al., 2019; Alphs
et al., 2018; Barrio et al., 2013; Emsley et al., 2008; Ibach &
Schreiner, 2008; Kim et al., 2008; Malla et al., 2016; Privat
 4

TABLE 1 Summary of included studies

Duration Patient population

Author, year n Study design (months) Diagnosis details Mean age (SD) (years) Medication Dosage Outcomes

Abdel-Baki LAI: 17OAP: 121 Naturalistic/ 36 First-episode Previous LAI: 24.2 (3.2)OAP: 23.6 NS NS Adherence,
et al., prospective & schizophrenia antipsychotic (3.8) discontinuation,
2019 retrospective (DSM-IV) with treatment: ≤1 year hospitalization,
study SUD (drug use Comorbid SUD: n = relapse
scale and slcohol 125 (89.9%)
use scale)
Alphs et al., LAI: 42OAP: 35 OL RCT 15 Recent-onset Mean duration of LAI: 30.8 (9.7) LAI: PP LAI:PP: 78– Discontinuation,
2018 schizophrenia (mini illness: OAP: 32.8 (10.9) OAP: ARI, HAL, OLA, 234 mg/month hospitalization
international LAI: ~2.9 years PAL, PER, QUE, OAP: NS
neuropsychiatric OAP: ~3.2 years RIS
Interview, version
6.0) with history of
criminal justice
system
involvement
Barrio et al., LAI: 26OAP: 26 Naturalistic/case– 24 Recent-onset Mean duration of LAI:26.9 (6.7) LAI: RIS LAI:RIS: 25– Hospitalization
2013 control study schizophrenia illness: OAP: 27.4 (7.5) OAP: OLA, RIS, CLO, 50 mg/2 weeks
(DSM-IV) LAI: ~1.2 yearsOAP: ZIP, ARI, PAL, OAP:
~0.4 years AMI, QUE Various dosages
Emsley et al., LAI: 50OAP: 47 Post-hoc 24 Early Mean duration of LAI: 25.4 (7.4) LAI: RIS LAI: Discontinuation,
2008 comparison schizophrenia, illness: ≤1 year and OAP: 25.9 (5.8) OAP: RIS, HAL RIS: 25– relapse
LAI: Prospective schizophreniform ≤2 psychiatric 50 mg/2 weeks
OL study disorder, hospitalizations OAP: RIS:
OAP: Double-blind schizoaffective Previous 1–8 mg/day
RCT disorder (DSM-IV) antipsychotic HAL: 1–8 mg/day
treatment:
≤12 weeks
Ibach & LAI: 113OAP: 117 Naturalistic study 24 Recent-onset Mean duration of LAI: 34.4 (NS) LAI: RISOAP: AMI, NS Discontinuation
Schreiner, schizophrenia illness: OAP: 34.3 (NS) ARI, OLA, QUE,
2008 (ICD-10) LAI: 2.8 (1.8) RIS, ZIP
yearsOAP: 2.4
(1.5) years
Kim et al., LAI: 22OAP: 28 Naturalistic/ 24 First-episode Mean duration of LAI: 32.5 (10.6) LAI: RIS LAI: Adherence, relapse
2008 controlled OL schizophrenia or illness: OAP: 31.0 (10.1) OAP: RIS RIS: 25–
study Schizoaffective LAI: 1.5 (1.5) years 50 mg/2 weeks
disorder (DSM-IV OAP: 2.2 (3.1) years OAP:RIS: 1–6 mg/
[SCID]) day
Malla et al., LAI: 42OAP: 35 OL RCT 24 Recent-onset Mean duration of LAI: 22.5 (3.1) LAI: RIS LAI: RIS: 25– Adherence,
2016 schizophrenia, illness: OAP: 23.0 (2.9) OAP: OLA, QUE, RIS 50 mg/2 weeks discontinuation,
schizophreniform, Total: ~9 (0.88) OAP:various hospitalization
schizoaffective months dosages
(DSM-IV [SCID])
Rifkin et al., LAI: 19OAP: 24 Double-blinded 12 Schizophrenia–any Mean number of LAI: 23.6 (range: 17-38)a LAI: FPZ LAI: FPZ: 0.5– Discontinuation,
1977 RCT subtype (diagnosis psychotic OAP: 23.8 (Range: 17-37)a OAP: FPZ 2.0 mL/2 weeks relapse
based on study episodes: OAP:FPZ: 5–
psychiatrist using Acute patients: 20 mg/day
criteria outlined in = 1 episode
Klein and Davis, Chronic patients:
1969) LAI: 1.67 episodes
LIAN ET AL.

OAP: 1.90 episodes

TABLE 1 (Continued)
Duration Patient population
Author, year n Study design (months) Diagnosis details Mean age (SD) (years) Medication Dosage Outcomes
LIAN ET AL.

Schreiner LAI: 352OAP: 363 Single-blinded RCT 24 Recent-onset Mean duration of LAI: 32.6 (10.7) LAI: PP LAI: Adherence,
et al., schizophrenia illness: OAP: 32.6 (10.1) OAP: ARI, HAL, OLA, PP: 25–150 mg/ discontinuation,
2015 (DSM-IV) LAI: 3.0 (1.7) years PAL, QUE, RIS monthOAP: relapse
OAP: 2.9 (1.5) years various dosages
Segarra LAI: 18 RCT 12 First episode NS NS LAI: RIS NS Hospitalization
et al., OAP: 21 psychosis OAP: RIS
2010
Subotnik LAI: 40 OL RCT 12 Recent-onset Mean duration of LAI: 21.9 (3.8)OAP: 21.1 LAI: RIS LAI: Adherence,
et al., OAP: 43 schizophrenia, illness: (3.2) OAP: RIS RIS: 12– discontinuation,
2015 schizoaffective LAI: 6.9 37.5 mg/ hospitalization,
disorder, (6.8) months 2 weeks relapse
depressed type, OAP: 7.9 (6.6) OAP:
schizophreniform months RIS: 1–7.5 mg/day
disorder (DSM-IV)
Privat et al., LAI: 11 Naturalistic study 6 First-episode Mean duration of LAI: 22.2 (3.6) LAI: PP, ZUC, RIS NS Hospitalization
2015 OAP: 177 schizophrenia, untreated OAP: 24.9 (5.0) OAP: OLA, ARI, PAL,
schizophreniform psychosis: AMI, QUE, CLO,
disorder, brief LAI: 70.1 RIS
psychotic disorder (65.4) days
(DSM-V) OAP: 109.5
(199.8) days
Taipale et al., ALL: 8719 Naturalistic/ 240 First-episode Patients hospitalized Total: median of 36.2 LAI: OLA, PP, PER, NS Hospitalization
2018 retrospective schizophrenia for the first time (range: 26.2–52.3) FPZ, ARI, FLU,
study (ICD-10, ICD-9, from 1996–2014 ZUC, RIS, HAL
ICD-8) Previous OAP: CLO, CPX,
antipsychotic FLU, OLA, ZUC,
treatment: No use LEV, ARI, RIS,
of antipsychotics HAL, PER, FPZ,
for 1 year THOR, QUE
preceding first
hospitalization
Titus-Lay LAI: 4 Naturalistic/ 12 Recent-onset Mean duration of Total: 21 (NS) LAI: PP NS Adherence
et al., OAP: 35 retrospective schizophrenia, illness: ≤2 years OAP: ARI, OLA, HAL,
2018 study schizophreniform FPZ, RIS
disorder,
schizoaffective
disorder, or
psychosis NOS
(DSM-IV)
Weiden LAI: 19 OL RCT 24 First-episode NS Total: 25.3 (6.6) LAI: RIS LAI: RIS: 25– Adherence,
et al., OAP: 18 schizophrenia, OAP: ARI, OLA, QUE, 50 mg/2 weeks discontinuation,
2012 schizophreniform, ZIP, RIS OAP: hospitalization
or schizoaffective various dosages
(DSM-IV [SCID])

Abbreviations: AMI, amisulpride; ARI, aripiprazole; CLO, clozapine; CPX, chlorprothixene; DSM, diagnostic and statistical manual; FLU, flupentixol; FPZ, fluphenazine; HAL, haloperidol; ICD, international statistical classification of diseases and
related health problems; LEV, levomepromazine; NOS, not otherwise specified; NS, not specified; OL, open-label; OLA, olanzapine; PAL, paliperidone; PER, perphenazine; PP, paliperidone palmitate; QUE, quetiapine; RCT, randomized controlled
trial; RIS, risperidoneSCID, structured clinical interview for DSM; SUD, substance use disorder; THOR, thioridazine; ZIP, ziprasidone; ZUC, zuclopenthixol.
a
Based on pooled schizophrenia and nonschizophrenia patient data.
5
6 LIAN ET AL.
et al., 2015; Rifkin et al., 1977; Schreiner et al., 2015; Segarra
et al., 2010; Subotnik et al., 2015; Taipale et al., 2018; Titus-Lay
et al., 2018; Weiden et al., 2012) (n = 10 584) comparing LAIs with
OAPs were selected to be included in the present meta-analysis.
Table 1 summarizes the characteristics of the included studies.
Seven of the studies were RCTs (Alphs et al., 2018; Malla
et al., 2016; Privat et al., 2015; Rifkin et al., 1977; Schreiner
et al., 2015; Segarra et al., 2010; Weiden et al., 2012), one was a post-
hoc comparison (Emsley et al., 2008), and the remaining were obser-
vational studies (Abdel-Baki et al., 2019; Barrio et al., 2013; Ibach &
Schreiner, 2008; Kim et al., 2008; Subotnik et al., 2015; Taipale
et al., 2018; Titus-Lay et al., 2018). Four of the RCTs were open-label
(Alphs et al., 2018; Malla et al., 2016; Subotnik et al., 2015; Weiden
et al., 2012), one was double-blinded (Rifkin et al., 1977), another was
single-blinded (Schreiner et al., 2015), and the remaining study did not
provide information about the blinding procedure (Segarra
et al., 2010). Two of the included studies (Ibach & Schreiner, 2008;
Segarra et al., 2010) were conference publications. Details of the risk
of bias assessment for the RCTs and observational studies is provided
in the Appendix S1. Overall, in RCTs, information pertaining to ran-
dom sequence generation and allocation concealment was largely
unclear, blinding was inadequately done, and the role of the funding
source was unclear or might have contributed bias in 5/7 studies
(Figure S1). In observational studies, other than mostly a low risk of
bias in measurement of outcomes and selection of the reported result,
at least a moderate or unclear risk of bias was detected in the rest of
the bias domains (Table S1).
The LAIs used in the studies included paliperidone (N = 5), risperi-
done (N = 10), olanzapine (N = 1), perphenazine (N = 1), fluphenazine
(N = 2), aripiprazole (N = 1), flupenthixol (N = 1), zuclopenthixol
(N = 2), and haloperidol (N = 1). The OAPs used included aripiprazole
(N = 8), amisulpride (N = 3) clozapine (N = 3), olanzapine (N = 9),
quetiapine (N = 8), risperidone (N = 13), chlorprothixene (N = 1), flu-
phenazine (N = 3), flupentixol (N = 1), haloperidol (N = 5),
levomepromazine (N = 1), perphenazine (N = 2), thioridazine (N = 1),
zuclopenthixol (N = 1), ziprasidone (N = 3), and paliperidone (N = 4).
The type of LAI and OAP used in one study (Abdel-Baki et al., 2019)
was not specified.
The number of participants per study ranged from 37 to 8719.
Amongst the included studies, the youngest reported age was a mean
of 21 (Titus-Lay et al., 2018), whilst the oldest was a median of 36.2
(Taipale et al., 2018). Study duration ranged from 6 months to 20 years.
In one study (Abdel-Baki et al., 2019), 89.9% (n = 125) of the included
participants had a comorbid substance use disorder. Another study
(Alphs et al., 2018) recruited recent-onset schizophrenia patients with a
history of criminal justice system involvement. The study by Rifkin and
colleagues (1977) included patients with more than one episode of psy-
chosis and were classified as chronic patients by the study authors.
However, when pooled together, the chronic patients had a mean num-
ber of previous episodes less than 2 (LAI: 1.67, ORAL: 1.90) and were
of relatively young age (LAI: 23.6 years, ORAL: 23.8 years). Therefore,
we assumed that these patients were in the early phase of schizophre-
nia and included the study in our analysis.
3.2 | Relapse rates
LAIs were nearly statistically significant for being superior to OAPs in
terms of relapse rates (N = 7, LAI: n = 539, OAP: n = 656, RR = .58,
95% CI = .34–1.01, Z = 1.93, p = .05; I2 = 77%) (Figure 2(a)). No sig-
nificant differences were found in the subgroup analysis of studies
including SGA LAIs (N = 6) compared to FGA LAIs (N = 1) (p = .70).
The subgroup analysis of observational (N = 3) compared to RCTs
(N = 4) demonstrated no significant differences (p = .55).
3.3 | Discontinuation rates
There were no significant differences found for all-cause discontinua-
tion rates between LAI and OAP groups (N = 9, LAI: n = 712, OAP:
n = 892, RR = .89, 95% CI = .72–1.09, Z = 1.11, p = .27; I2 = 62%)
(Figure 2(b)). A significant subgroup difference was found (p = .01)
based on studies examining SGA LAIs (N = 8) versus FGA LAIs
(N = 1), favouring SGA LAIs. No significant difference was found
(p = 0.34) in the subgroup analysis comparing observational studies
(N = 3) to RCTs (N = 6).
LAIs were found to be superior to OAPs with respect to discon-
tinuation due to nonadherence (N = 2, LAI: n = 394, OAP: n = 398,
RR = .31, 95% CI = .11–.87, Z = 2.24, p = .03; I2 = 0%) and inefficacy
(N = 4, LAI: n = 476, OAP: n = 475, RR = .35, 95% CI = .13–.96,
Z = 2.05, p = .04; I2 = 0%).
No significant differences were found for discontinuation due to
adverse effects between LAI and OAP groups (N = 5, LAI: n = 499, OAP:
n = 503, RR = 1.59, 95% CI = .62–4.07, Z = .97, p = .33; I2 = 53%). No
significant differences were found in the subgroup analysis of studies
including SGAs (N = 4) compared to FGAs (N = 1) (p = .09).
3.4 | Adherence rates
There were no significant differences found for adherence
rates between LAI and OAP groups (N = 7, LAI: n = 510, OAP:
n = 728, RR = 1.50, 95% CI = 0.79–2.86, Z = 1.24, p = .21;
I2 = 97%) (Figure 2(c)). In the subgroup analysis comparing RCTs
(N = 4) to observational studies (N = 3), no significant differences
were found (p = .99).
3.5 | Hospitalization rates
There were no significant differences found for hospitalization
rates between LAI and OAP groups (N = 9, LAI: n = 2890, OAP:
n = 32 886, OR = .57, 95% CI = .30–1.08, Z = 1.72, p = .08,
I2 = 67%) (Figure 2(d)). As the study by (Privat et al., 2015) reported
hospitalization rate as a continuous outcome, the generic inverse-
variance method in RevMan was used to combine the log odds ratios
of all the studies. Additionally, the hospitalization rate for the study
conducted by (Taipale et al., 2018) was calculated in terms of the
LIAN ET AL.
F I G U R E 2 Forests plots comparing long-acting injectable versus oral antipsychotics in terms of (a) relapse rate, (b) all-cause discontinuation
rate, (c) adherence rate, and (d) hospitalization rate
number of events per person-years. This was done because the follow-
up duration varied amongst the participants in the study. Although the
use of person-years caused the study by (Taipale et al., 2018) to carry a
large amount of weight (21.1%) in our analysis, excluding the study did
not cause significant changes in the overall effect.
After separating RCTs from observational studies, LAIs were
found to be superior to OAPs in RCTs (N = 6, LAI: n = 172, OAP:
n = 329, OR = .3799, 95% CI = .1447–.9975, Z = 1.97, p = .05,
I2 = 52%). No significant differences were found for the subgroup
analysis comparing observational studies (N = 3) to RCTs (N = 6)
(p = .13). The subgroup analysis comparing studies using SGA LAIs
(N = 9) versus those that included FGA LAIs (N = 1) demonstrated a
significant difference (p = .04), favouring SGA LAIs.
4 | DISCUSSION
To our knowledge, this meta-analysis is the first to compare the effi-
cacy of LAIs and OAPs in early stages of psychosis using both RCTs
and observational studies. Our results indicate that LAIs may provide
advantages over OAPs in terms of relapse rates. After separating
RCTs from observational studies in a subgroup analysis, the results
indicated that LAIs were superior to OAPs in terms of hospitalization
rates for RCTs. However, no differences were found between LAI-
and OAP-treated groups in terms of all-cause discontinuation and
7
adherence rates. Results of recent meta-analyses comparing LAIs
and OAPs in terms of relapse rates are heterogeneous, with several
finding no significant differences between formulations (Kishimoto
et al., 2014; Ostuzzi et al., 2017), whilst another found that LAIs sig-
nificantly reduced relapse rates (Leucht et al., 2011). In terms of all-
cause discontinuation, recent meta-analyses of RCTs have found no
significant differences between LAIs and OAPs (Leucht et al., 2011;
Ostuzzi et al., 2017), whilst another meta-analysis of prospective and
retrospective cohort studies found that LAIs were superior to OAPs
(Kishimoto et al., 2018). Results of meta-analyses comparing LAIs and
OAPs in terms of hospitalization rates are also heterogenous, with
several showing that LAIs are superior to OAPs in terms of hospitali-
zation rates (Kishimoto et al., 2013; Kishimoto et al., 2018), and
another finding no significant differences between the two formula-
tions (Park et al., 2018). However, these meta-analyses did not exclu-
sively include studies investigating antipsychotic usage in early stages
of psychosis. (Kishi et al., 2016) conducted the only other meta-
analysis to date that evaluated the efficacy of LAIs in patients with
recent-onset psychotic disorders. This meta-analysis included five
RCTs (n = 1022) and compared paliperidone or risperidone LAIs with
OAPs. Consistent with our findings, they also found no significant dif-
ferences between LAI and OAP groups in terms of all-cause discontin-
uation and discontinuation due to adverse events, and that LAIs were
superior to OAPs in terms of discontinuation due to inefficacy. In con-
trast to our findings, they found no significant differences between
8 LIAN ET AL.
LAIs and OAPs with respect to relapse rates (Kishi et al., 2016). The
authors discussed that this result may be a statistical type II error,
because only three studies were included in their analysis of relapse
rates (Kishi et al., 2016). In addition, there was significant heterogene-
ity present, with the one study showing that LAIs were not superior
to OAPs, giving the lowest statistical power (Kishi et al., 2016). In
addition to the three RCTs (Malla et al., 2016; Schreiner et al., 2015;
Subotnik et al., 2015) that (Kishi et al., 2016) included in their analysis
of relapse rates, we included one double-blind RCT (Rifkin
et al., 1977), two observational studies (Abdel-Baki et al., 2019; Kim
et al., 2008), and one post-hoc analysis (Emsley et al., 2008). There-
fore, stronger conclusions may be drawn from the results of our meta-
analysis.
With regards to the heterogeneity observed in our meta-analysis,
some studies need to be discussed. The (Abdel-Baki et al., 2019) study
included a large number of patients with substance use disorder,
which has been shown to be associated with nonadherence to medi-
cation (Verdoux et al., 2000). Therefore, the results observed may be
due to the poorer prognostic factors of those treated with LAIs
coupled with the presence of comorbid substance use disorder. The
(Abdel-Baki et al., 2019) study likely showed that more patients
treated with LAIs relapsed for the same reason that lower adherence
rates were observed in this group. Although the (Malla et al., 2016)
study showed that more participants taking LAIs relapsed compared
with those taking OAPs, they found no significant differences in time
to relapse or time to achieve stabilization. The (Malla et al., 2016)
study also discussed that the lack of superiority of using LAIs, found
in terms of relapse prevention, may be due to the restriction they
placed on raising the dosage of risperidone LAI beyond 50 mg,
whereas there was no dosage limit placed on OAPs. The definition of
adherence and relapse used by the study authors was also heteroge-
nous. The (Rifkin et al., 1977) study included FGAs, which have been
shown to have higher treatment discontinuation rates and cause more
extrapyramidal symptoms compared with SGAs (Zhang et al., 2013).
This is supported by the fact that the subgroup analysis comparing
FGAs and SGAs showed significant differences (p = .01). As discussed
previously, the poorer prognostic factors amongst those treated with
LAIs in the (Abdel-Baki et al., 2019) study likely led to the greater dis-
continuation rate observed in the LAI group.
Long-acting injectable antipsychotics require patients to have reg-
ular contact with medical staff, which may result in improved adher-
ence rates (Patel & David, 2005). In addition, LAIs allow clinicians to
take immediate action to prevent relapse if patients do not show up
to their injection appointment (Weiden & Glazer, 1997). Discontinua-
tion of antipsychotics is common in early psychosis patients and it has
been demonstrated that discontinuing medication increases the risk
of relapse significantly (Hui et al., 2018; Robinson et al., 1999). As our
results indicate that LAIs may provide advantages over OAPs with
respect to reducing relapse rates, clinicians may consider using LAIs as
a treatment following a first psychotic episode to minimize the likeli-
hood of negative clinical outcomes. However, many clinicians prefer
prescribing OAPs over LAIs following a first psychotic episode and do
not consider LAIs to have significant advantages over OAPs (Jaeger &
Rossler, 2010). In addition, patients have been reported to believe
that LAIs will limit their freedom, and that administration of the injec-
tion will be painful (Das et al., 2014; Grover et al., 2019). However,
these negative perceptions may be due to the lack of information
about LAIs provided to patients (Jaeger & Rossler, 2010). Therefore,
efforts should be made to increase patient awareness on the different
medication options available to them.
There are several limitations in the present meta-analysis that
should be considered. First, the number of studies included in our
analysis is relatively modest (N = 15) and does not allow for categori-
cal conclusions to be drawn. Second, this meta-analysis includes non-
randomized observational studies which may introduce prescribing
bias (Haddad et al., 2015). However, we ensured that there was no
significant subgroup difference between the two study types. Third,
the included RCTs were generally of low quality in terms of selection,
performance, detection, and other bias. Fourth, as testing for funnel
plot asymmetry only provides meaningful information when there are
at least ten studies included, we did not include this plot to evaluate
reporting bias (Higgins & Green, 2011). Finally, there was significant
heterogeneity (I2 > 50%) in all of our primary outcomes. In addition,
the exact nature of discontinuation due to adverse events could not
be reported with a fine granularity. A wide range of adverse events
are associated with antipsychotic drugs, including cardiometabolic
effects (Boyda et al., 2013; Kim et al., 2017; Kim et al., 2018; Tse
et al., 2014; Yuen et al., 2018; Yuen et al., 2021), and it would be
informative to determine which adverse events cause drug discontin-
uation in early psychosis.
5 | CONC LU SION
Overall, there is a lack of consensus amongst previous meta-analyses
on the superiority of LAIs over OAPs in treating psychosis. Interest-
ingly, RCTs often show no difference in efficacy between LAIs and
OAPs, whilst observational studies show that LAIs are superior to
OAPs (Haddad et al., 2015). Both RCTs and observational studies
have their own inherent weaknesses. To better compare the clinical
efficacy of LAIs with OAPs, an RCT with a broad inclusion criterion
and with minimal assessments following baseline tests and randomiza-
tion should be conducted in order to reduce selection bias and alter-
ations of the ecology of treatment (Haddad et al., 2015). To conclude,
LAIs may provide advantages over OAPs in terms of relapse preven-
tion and risk of hospitalization during early stages of psychosis. How-
ever, additional studies that include a larger number of early-stage
psychosis patients and minimize risk of bias are needed in order to
draw strong conclusions on the benefits of LAIs over OAPs.
CONFLIC T OF INT ER E ST
W. Honer has received consulting fees or sat on paid advisory boards
for the Canadian Agency for Drugs and Technology in Health,
AlphaSights, In Silico (unpaid), Newron, Translational Life Sciences
and Otsuka/Lundbeck. R. Procyshyn has received consulting fees or
sat on paid advisory boards for Janssen, Lundbeck and Otsuka; is on
LIAN ET AL.
the speaker's bureau for Janssen, Lundbeck and Otsuka. D. Fredrikson
has sat on paid advisory boards or on speaker's bureau for Janssen,
Lundbeck, and Otsuka. L. Lian, D. Kim, D. Cázares and A. Barr have no
conflict of interest to declare.
ORCID
Alasdair M. Barr https://orcid.org/0000-0002-3407-1574
RE FE R ENC E S
Abdel-Baki, A., Thibault, D., Medrano, S., Stip, E., Ladouceur, M.,
Tahir, R., & Potvin, S. (2019). Long-acting antipsychotic medication as
first-line treatment of first-episode psychosis with comorbid substance
use disorder. Early Intervention in Psychiatry, 14(1), 69–79. https://doi.
org/10.1111/eip.12826
Alphs, L., Bossie, C., Mao, L., Lee, E., & Starr, H. L. (2018). Treatment effect
with paliperidone palmitate compared with oral antipsychotics in
patients with recent-onset versus more chronic schizophrenia and a
history of criminal justice system involvement. Early Intervention in Psy-
chiatry, 12(1), 55–65. https://doi.org/10.1111/eip.12271
Barrio, P., Batalla, A., Castellví, P., Hidalgo, D., García, M., Ortiz, A.,
Grande, I., Pons, A., & Parellada, E. (2013). Effectiveness of long-acting
injectable risperidone versus oral antipsychotics in the treatment of
recent-onset schizophrenia: A case-control study. International Clinical
Psychopharmacology, 28(4), 164–170. https://doi.org/10.1097/YIC.
0b013e3283611cc3
Boyda, H. N., Procyshyn, R. M., Pang, C. C., Hawkes, E., Wong, D.,
Jin, C. H., Honer, W. G., & Barr, A. M. (2013). Metabolic side-effects of
the novel second-generation antipsychotic drugs asenapine and
iloperidone: A comparison with olanzapine. PLoS One, 8(1), e53459.
Coldham, E. L., Addington, J., & Addington, D. (2002). Medication adher-
ence of individuals with a first episode of psychosis. Acta Psychiatrica
Scandinavica, 106(4), 286–290. https://doi.org/10.1034/j.1600-0447.
2002.02437.x
Correll, C. U., Citrome, L., Haddad, P. M., Lauriello, J., Olfson, M.,
Calloway, S. M., & Kane, J. M. (2016). The use of long-acting injectable
antipsychotics in schizophrenia: Evaluating the evidence. Journal of
Clinical Psychiatry, 77(suppl 3), 1–24. https://doi.org/10.4088/JCP.
15032su1
Das, A. K., Malik, A., & Haddad, P. M. (2014). A qualitative study of
the attitudes of patients in an early intervention service towards
antipsychotic long-acting injections. Therapeutic Advances in Psy-
chopharmacology, 4(5), 179–185. https://doi.org/10.1177/
2045125314542098
Dufort, A., & Zipursky, R. B. (2019). Understanding and managing treat-
ment adherence in schizophrenia. Clinical Schizophrenia & Related Psy-
choses. https://doi.org/10.3371/csrp.adrz.121218
Emsley, R., Oosthuizen, P., Koen, L., Niehaus, D. J., Medori, R., &
Rabinowitz, J. (2008). Oral versus injectable antipsychotic treatment in
early psychosis: Post hoc comparison of two studies. Clinical Therapeu-
tics, 30(12), 2378–2386. https://doi.org/10.1016/j.clinthera.2008.
12.020
Friis, S., Melle, I., Johannessen, J. O., Røssberg, J. I., Barder, H. E.,
Evensen, J. H., Haahr, U., ten Velden Hegelstad, W., Joa, I.,
Langeveld, J., Larsen, T. K., Opjordsmoen, S., Rund, B. R., Simonsen, E.,
Vaglum, P. W., & McGlashan, T. H. (2016). Early predictors of ten-year
course in first-episode psychosis. Psychiatric Services, 67(4), 438–443.
https://doi.org/10.1176/appi.ps.201400558
Gerlach, J. (1994). Oral versus depot administration of neuroleptics in
relapse prevention. Acta Psychiatrica Scandinavica, 382, 28–32.
Grover, S., Sahoo, S., Bn, S., Malhotra, N., Dua, D., & Avasthi, A. (2019).
Attitude and perceptions of patients towards long acting depot injec-
tions (LAIs). Asian Journal of Psychiatry, 44, 200–208. https://doi.org/
10.1016/j.ajp.2019.07.052
9
Haddad, P. M., Kishimoto, T., Correll, C. U., & Kane, J. M. (2015). Ambigu-
ous findings concerning potential advantages of depot antipsychotics:
In search of clinical relevance. Current Opinion in Psychiatry, 28(3),
216–221. https://doi.org/10.1097/yco.0000000000000160
Hany, M., Rehman, B., & Chapman, J. (2019). Schizophrenia. In StatPearls.
StatPearls Publishing StatPearls Publishing LLC.
Hickling, L. M., Kouvaras, S., Nterian, Z., & Perez-Iglesias, R. (2018). Non-
adherence to antipsychotic medication in first-episode psychosis
patients. Psychiatry Research, 264, 151–154. https://doi.org/10.1016/
j.psychres.2018.04.002
Higgins, J. P., Thompson, S. G., Deeks, J. J., & Altman, D. G. (2003). Mea-
suring inconsistency in meta-analyses. BMJ, 327(7414), 557–560.
https://doi.org/10.1136/bmj.327.7414.557
Higgins, J. P. T., & Green, S. (2011). Cochrane handbook for systematic
reviews of interventions. John Wiley & Sons.
Hui, C. L., Tang, J. Y., Leung, C. M., Wong, G. H., Chang, W. C., Chan, S. K.,
Lee, E. H., & Chen, E. Y. (2013). A 3-year retrospective cohort study of
predictors of relapse in first-episode psychosis in Hong Kong.
Australian and New Zealand Journal of Psychiatry, 47(8), 746–753.
https://doi.org/10.1177/0004867413487229
Hui, C. L. M., Honer, W. G., Lee, E. H. M., Chang, W. C., Chan, S. K. W.,
Chen, E. S. M., Pang, E. P. F., Lui, S. S. Y., Chung, D. W. S.,
Yeung, W. S., Ng, R. M. K., Lo, W. T. L., Jones, P. B., Sham, P., &
Chen, E. Y. H. (2018). Long-term effects of discontinuation from anti-
psychotic maintenance following first-episode schizophrenia and
related disorders: A 10 year follow-up of a randomised, double-blind
trial. Lancet Psychiatry, 5(5), 432–442. https://doi.org/10.1016/
s2215-0366(18)30090-7
Ibach, B., & Schreiner, A. (2008). Interim-analysis of a long-term treatment
study with long-acting injectable risperidone and oral second-
generation antipsychotics in schizophrenia. European
Neuropsychopharmacology, 18, S437. https://doi.org/10.1016/s0924-
977x(08)70642-4
Iyer, S., Jordan, G., MacDonald, K., Joober, R., & Malla, A. (2015). Early
intervention for psychosis: A Canadian perspective. The Journal of Ner-
vous and Mental Disease, 203(5), 356–364. https://doi.org/10.1097/
nmd.0000000000000288
Jaeger, M., & Rossler, W. (2010). Attitudes towards long-acting depot anti-
psychotics: A survey of patients, relatives and psychiatrists. Psychiatry
Research, 175(1–2), 58–62. https://doi.org/10.1016/j.psychres.2008.
11.003
Kane, J. M., Kishimoto, T., & Correll, C. U. (2013). Non-adherence to medi-
cation in patients with psychotic disorders: Epidemiology, contributing
factors and management strategies. World Psychiatry, 12(3), 216–226.
https://doi.org/10.1002/wps.20060
Keating, D., McWilliams, S., Schneider, I., Hynes, C., Cousins, G.,
Strawbridge, J., & Clarke, M. (2017). Pharmacological guidelines for
schizophrenia: A systematic review and comparison of recommenda-
tions for the first episode. BMJ Open, 7(1), e013881. https://doi.org/
10.1136/bmjopen-2016-013881
Kim, B., Lee, S. H., Choi, T. K., Suh, S., Kim, Y. W., Lee, E., & Yook, K. H.
(2008). Effectiveness of risperidone long-acting injection in first-
episode schizophrenia: In naturalistic setting. Progress in Neuro-
Psychopharmacology & Biological Psychiatry, 32(5), 1231–1235.
https://doi.org/10.1016/j.pnpbp.2008.03.012
Kim, D. D., Lang, D. J., Warburton, D. E., Barr, A. M., Smith, G. N.,
Thornton, A. E., White, R. F., Honer, W. G., & Procyshyn, R. M. (2017).
Effects of exercise on serum triglycerides and symptoms of schizo-
phrenia. Journal of Clinical Psychopharmacology, 37(2), 273–274.
https://doi.org/10.1097/jcp.0000000000000648
Kim, D. D., White, R. F., Barr, A. M., Honer, W. G., & Procyshyn, R. M.
(2018). Clozapine, elevated heart rate and QTc prolongation. Journal of
Psychiatry & Neuroscience, 43(1), 71–72.
Kishi, T., Oya, K., & Iwata, N. (2016). Long-acting injectable antipsychotics
for the prevention of relapse in patients with recent-onset psychotic
10
disorders: A systematic review and meta-analysis of randomized con-
trolled trials. Psychiatry Research, 246, 750–755. https://doi.org/10.
1016/j.psychres.2016.10.053
Kishimoto, T., Hagi, K., Nitta, M., Leucht, S., Olfson, M., Kane, J. M., &
Correll, C. U. (2018). Effectiveness of long-acting injectable vs Oral
antipsychotics in patients with schizophrenia: A meta-analysis of pro-
spective and retrospective cohort studies. Schizophrenia Bulletin, 44(3),
603–619. https://doi.org/10.1093/schbul/sbx090
Kishimoto, T., Nitta, M., Borenstein, M., Kane, J. M., & Correll, C. U.
(2013). Long-acting injectable versus oral antipsychotics in schizophre-
nia: A systematic review and meta-analysis of mirror-image studies.
Journal of Clinical Psychiatry, 74(10), 957–965. https://doi.org/10.
4088/JCP.13r08440
Kishimoto, T., Robenzadeh, A., Leucht, C., Leucht, S., Watanabe, K.,
Mimura, M., Borenstein, M., Kane, J. M., & Correll, C. U. (2014). Long-
acting injectable vs oral antipsychotics for relapse prevention in
schizophrenia: A meta-analysis of randomized trials. Schizophrenia Bul-
letin, 40(1), 192–213. https://doi.org/10.1093/schbul/sbs150
Klein, D. F., & Davis, J. M. (1969). Diagnosis and drug treatment of psychi-
atric disorders. Baltimore: Williams & Wilkins.
Larsen, T. K., Moe, L. C., Vibe-Hansen, L., & Johannessen, J. O. (2000).
Premorbid functioning versus duration of untreated psychosis in 1 year
outcome in first-episode psychosis. Schizophrenia Research, 45(1–2),
1–9.
Leucht, C., Heres, S., Kane, J. M., Kissling, W., Davis, J. M., & Leucht, S.
(2011). Oral versus depot antipsychotic drugs for schizophrenia–A
critical systematic review and meta-analysis of randomised long-term
trials. Schizophrenia Research, 127(1–3), 83–92. https://doi.org/10.
1016/j.schres.2010.11.020
Linton, D., Barr, A. M., Honer, W. G., & Procyshyn, R. M. (2013). Antipsy-
chotic and psychostimulant drug combination therapy in attention def-
icit/hyperactivity and disruptive behavior disorders: A systematic
review of efficacy and tolerability. Current Psychiatry Reports, 15
(5), 355.
Malla, A., Chue, P., Jordan, G., Stip, E., Koczerginski, D., Milliken, H.,
Joseph, A., Williams, R., Adams, B., Manchanda, R., Oyewumi, K., &
Roy, M. A. (2016). An exploratory, open-label, randomized trial com-
paring risperidone long-acting injectable with Oral antipsychotic medi-
cation in the treatment of early psychosis. Clinical Schizophrenia &
Related Psychoses, 9(4), 198–208. https://doi.org/10.3371/csrp.mach.
061213
Moher, D., Liberati, A., Tetzlaff, J., & Altman, D. G. (2009). Preferred
reporting items for systematic reviews and meta-analyses: The PRI-
SMA statement. Open Med, 3(3), e123–e130.
Murru, A., & Carpiniello, B. (2018). Duration of untreated illness as a key
to early intervention in schizophrenia: A review. Neuroscience Letters,
669, 59–67. https://doi.org/10.1016/j.neulet.2016.10.003
Nordentoft, M., Rasmussen, J. O., Melau, M., Hjorthoj, C. R., &
Thorup, A. A. (2014). How successful are first episode programs? A
review of the evidence for specialized assertive early intervention.
Current Opinion in Psychiatry, 27(3), 167–172.
Ostuzzi, G., Bighelli, I., So, R., Furukawa, T. A., & Barbui, C. (2017). Does
formulation matter? A systematic review and meta-analysis of oral
versus long-acting antipsychotic studies. Schizophrenia Research, 183,
10–21. https://doi.org/10.1016/j.schres.2016.11.010
Park, S. C., Choi, M. Y., Choi, J., Park, E., Tchoe, H. J., Suh, J. K., Kim, Y. H.,
Won, S. H., Chung, Y. C., Bae, K. Y., Lee, S. K., Park, C. M., & Lee, S. H.
(2018). Comparative efficacy and safety of long-acting injectable and
Oral second-generation antipsychotics for the treatment of schizo-
phrenia: A systematic review and meta-analysis. Clin Psychopharmacol
Neurosci, 16(4), 361–375. https://doi.org/10.9758/cpn.2018.16.4.361
Patel, M. X., & David, A. S. (2005). Why aren't depot antipsychotics pre-
scribed more often and what can be done about it? Advances in Psychi-
atric Treatment, 11(3), 203–211.
LIAN ET AL.
Perkins, D. O., Gu, H., Boteva, K., & Lieberman, J. A. (2005). Relationship
between duration of untreated psychosis and outcome in first-episode
schizophrenia: A critical review and meta-analysis. American Journal of
Psychiatry, 162(10), 1785–1804. https://doi.org/10.1176/appi.ajp.
162.10.1785
Pietrini, F., Albert, U., Ballerini, A., Calò, P., Maina, G., Pinna, F.,
Vaggi, M., Boggian, I., Fontana, M., Moro, C., & Carpiniello, B. (2019).
The modern perspective for long-acting injectables antipsychotics in
the patient-centered care of schizophrenia. Neuropsychiatric Disease
and Treatment, 15, 1045–1060. https://doi.org/10.2147/ndt.
s199048
Privat, A. T., Baquero, D. B., Santacana, A. M., & Sola, V. P. (2015).
Decreased incidence of readmissions in first episode psychosis in
treatment with long - acting injectable antipsychotics. Current Psycho-
pharmacology, 4(1), 52–57.
Procyshyn, R. M., Barr, A. M., Flynn, S., Schenk, C., Ganesan, S., &
Honer, W. G. (2010). Long-acting injectable risperidone in treatment
refractory patients: A 14-week open-label pilot study. Schizophrenia
Research, 123(2–3), 273–275.
Remington, G., Addington, D., Honer, W., Ismail, Z., Raedler, T., &
Teehan, M. (2017). Guidelines for the pharmacotherapy of schizophre-
nia in adults. Canadian Journal of Psychiatry, 62(9), 604–616. https://
doi.org/10.1177/0706743717720448
Rifkin, A., Quitkin, F., Rabiner, C. J., & Klein, D. F. (1977). Fluphenazine
decanoate, fluphenazine hydrochloride given orally, and placebo in
remitted schizophrenics. I. Relapse rates after one year. Archives of
General Psychiatry, 34(1), 43–47. https://doi.org/10.1001/archpsyc.
1977.01770130045004
Robinson, D., Woerner, M. G., Alvir, J. M., Bilder, R., Goldman, R.,
Geisler, S., Koreen, A., Sheitman, B., Chakos, M., Mayerhoff, D., &
Lieberman, J. A. (1999). Predictors of relapse following response from
a first episode of schizophrenia or schizoaffective disorder. Archives of
General Psychiatry, 56(3), 241–247. https://doi.org/10.1001/archpsyc.
56.3.241
Schreiner, A., Aadamsoo, K., Altamura, A. C., Franco, M., Gorwood, P.,
Neznanov, N. G., Schronen, J., Ucok, A., Zink, M., Janik, A.,
Cherubin, P., Lahaye, M., & Hargarter, L. (2015). Paliperidone palmitate
versus oral antipsychotics in recently diagnosed schizophrenia. Schizo-
phrenia Research, 169(1–3), 393–399. https://doi.org/10.1016/j.
schres.2015.08.015
Segarra, R., Ojeda, N., Garcia, J., Pena, J., Bravo, E., & Eguiluz, J. I. (2010).
Risperidone injectable long acting treatment vs other oral antipsy-
chotics in first episode psychosis: One year longitudinal study. Schizo-
phrenia Research, 117(2–3), 495.
Sterne, J. A., Hernán, M. A., Reeves, B. C., Savovic, J., Berkman, N. D.,
Viswanathan, M., & Higgins, J. P. (2016). ROBINS-I: a tool for
assessing risk of bias in non-randomised studies of interventions. BMJ,
355, i4919. https://doi.org/10.1136/bmj.i4919
Subotnik, K. L., Casaus, L. R., Ventura, J., Luo, J. S., Hellemann, G. S.,
Gretchen-Doorly, D., Marder, S., & Nuechterlein, K. H. (2015). Long-
acting injectable risperidone for relapse prevention and control of
breakthrough symptoms after a recent first episode of schizophrenia.
A randomized clinical trial. JAMA Psychiatry, 72(8), 822–829. https://
doi.org/10.1001/jamapsychiatry.2015.0270
Taipale, H., Mehtala, J., Tanskanen, A., & Tiihonen, J. (2018). Comparative
effectiveness of antipsychotic drugs for Rehospitalization in
schizophrenia-a Nationwide study with 20-year follow-up. Schizophre-
nia Bulletin, 44(6), 1381–1387. https://doi.org/10.1093/schbul/
sbx176
Takeuchi, H., Siu, C., Remington, G., Fervaha, G., Zipursky, R. B.,
Foussias, G., & Agid, O. (2019). Does relapse contribute to treatment
resistance? Antipsychotic response in first- vs. second-episode schizo-
phrenia. Neuropsychopharmacology, 44(6), 1036–1042. https://doi.
org/10.1038/s41386-018-0278-3
LIAN ET AL.
Titus-Lay, E. N., Ansara, E. D., Isaacs, A. N., & Ott, C. A. (2018). Evaluation
of adherence and persistence with oral versus long-acting injectable
antipsychotics in patients with early psychosis. Ment Health Clin, 8(2),
56–62. https://doi.org/10.9740/mhc.2018.03.056
Tse, L., Procyshyn, R. M., Fredrikson, D. H., Boyda, H. N., Honer, W. G., &
Barr, A. M. (2014). Pharmacological treatment of antipsychotic-
induced dyslipidemia and hypertension. International Clinical Psycho-
pharmacology, 29(3), 125–137.
Verdoux, H., Lengronne, J., Liraud, F., Gonzales, B., Assens, F., Abalan, F., &
van Os, J. (2000). Medication adherence in psychosis: Predictors and
impact on outcome. A 2-year follow-up of first-admitted subjects. Acta
Psychiatrica Scandinavica, 102(3), 203–210. https://doi.org/10.1034/j.
1600-0447.2000.102003203.x
Weiden, P., & Glazer, W. (1997). Assessment and treatment selection for
"revolving door" inpatients with schizophrenia. Psychiatric Quarterly,
68(4), 377–392.
Weiden, P. J., Schooler, N. R., Weedon, J. C., Elmouchtari, A., & Sunakawa-
McMillan, A. (2012). Maintenance treatment with long-acting inject-
able risperidone in first-episode schizophrenia: A randomized effec-
tiveness study. Journal of Clinical Psychiatry, 73(9), 1224–1233.
https://doi.org/10.4088/JCP.11m06905
Whitney, Z., Procyshyn, R. M., Fredrikson, D. H., & Barr, A. M. (2015).
Treatment of clozapine-associated weight gain: A systematic review.
European Journal of Clinical Pharmacology, 71(4), 389–401. https://doi.
org/10.1007/s00228-015-1807-1
Yuen, J. W. Y., Kim, D. D., Procyshyn, R. M., Panenka, W. J.,
Honer, W. G., & Barr, A. M. (2021). A focused review of the metabolic
11
side-effects of clozapine. Front Endocrinol, 12, 609240. https://doi.
org/10.3389/fendo.2021.609240
Yuen, J. W. Y., Kim, D. D., Procyshyn, R. M., White, R. F., Honer, W. G., &
Barr, A. M. (2018). Clozapine-induced cardiovascular side effects and
autonomic dysfunction: A systematic review. Frontiers in Neuroscience,
12, 203. https://doi.org/10.3389/fnins.2018.00203
Zhang, J. P., Gallego, J. A., Robinson, D. G., Malhotra, A. K., Kane, J. M., &
Correll, C. U. (2013). Efficacy and safety of individual second-generation
vs. first-generation antipsychotics in first-episode psychosis: A systematic
review and meta-analysis. International Journal of Neuropsychopharmacology,
16(6), 1205–1218. https://doi.org/10.1017/s1461145712001277
SUPPORTING INF ORMATION
Additional supporting information may be found online in the
Supporting Information section at the end of this article.
How to cite this article: Lian, L., Kim, D. D., Procyshyn, R. M.,
Fredrikson, D. H., Cázares, D., Honer, W. G., & Barr, A. M.
(2021). Efficacy of long-acting injectable versus oral
antipsychotic drugs in early psychosis: A systematic review
and meta-analysis. Early Intervention in Psychiatry, 1–11.
https://doi.org/10.1111/eip.13202